Finding a cure for a rare and debilitating genetic disease

DevelopAKUre is a European Union (EU)-funded research project which is working to establish a safe, reliable treatment for a rare and hitherto incurable disease. Caused by a genetic mutation, Alkaptonuria (AKU) leads to a severe and early-onset form of osteoarthritis and can also cause heart problems.

DevelopAKUre is a European Union (EU)-funded research project which is working to establish a safe, reliable treatment for a rare and hitherto incurable disease. Caused by a genetic mutation, Alkaptonuria (AKU) leads to a severe and early-onset form of osteoarthritis and can also cause heart problems.

AKU sufferers have an enzyme deficiency which leaves them unable to break down a naturally occurring substance within the body known as homogentisic acid, or HGA. HGA builds up in body tissues, in particular attacking cartilage and making it brittle. As the cartilage degenerates, patients quickly suffer from increasingly painful joint movements, to a point which can become extremely debilitating.

Not only is there currently no cure for AKU, there is also no effective palliative treatment. Patients are in constant pain and the only – far from satisfactory - options are permanent pain-relief, physiotherapy or serious interventions such as joint replacement or, in the case of heart problems, valve replacement.

The focus of the five-and-a-half year DevelopAKUre project, which began work in November 2012, is a highly promising drug called nitisinone. Licensed for the treatment of another rare disease, Hereditary Tyrosinemia Type 1, nitisinone is not yet approved for the treatment of AKU. Its attraction to the DevelopAKUre team is that it is known to stop the production of HGA.

“It decreases HGA to near normal levels,” says DevelopAKUre’s project co-ordinator, Professor Lakshminarayan Ranganath, of the Royal Liverpool and Broadgreen University Hospitals NHS Trust in the UK. “We developed a mouse model and we found that if we start mice with nitisinone from birth they never get the damage associated with AKU. If we wait until the damage starts and then begin nitisinone, it stops the damage in its tracks. So we are quite excited about this.”

The DevelopAKUre consortium consists of a group of specialist partners which have already worked together for many years and established a world-leading position in AKU research. It includes patient groups, small- and medium-sized enterprises (SMEs) providing biomarker analysis and clinical trial co-ordination, a larger commercial partner providing the drug, three universities for data analysis and three clinical trial centres in the UK, France and Slovakia.

The fact that DevelopAKUre is a pan-European project, supported by EU funding and with participants from 7 European countries is important not only because it brings together the elite talents of European AKU research, but also, crucially, because it gives access to a large enough sample of patients. Since AKU is a ‘recessive’ disease, which means that the AKU gene must be passed on by both of the patient’s parents, the disease is rare and the number of patients in any single country is low. It is estimated that AKU affects one in every 250,000 to 500,000 people, although in some countries it appears to be more common than this.

DevelopAKUre will undertake three distinct tasks as it seeks to establish the case for nitisinone to be licensed as a treatment for AKU. The first will be a four-week dose-response study to establish the optimum dosage of the drug. The second phase, using the dosage determined in phase one, will be a four-year clinical trial involving 140 AKU patients, conducted at the three trial centres in the UK, France and Slovakia. Patients will be divided into two groups, one receiving nitisinone and the other not, and closely monitored to see whether nitisinone is effective and safe as a treatment.

The third phase of the project centres around the fact that, although AKU is present from birth, its effects do not show until patients reach their 30s and it is not known if HGA build-up occurs before that point. DevelopAKUre researchers will investigate when HGA begins to accumulate, based on the fact that affected tissue takes on a black discolouration and is therefore easily identified. This will allow doctors to decide the most beneficial age at which treatment should be started.

“Hopefully,” says Professor Ranganath, “if all of these results are positive, the idea is that we will be able to go to the European Medicines Agency in 2018 and they will license nitisinone as a treatment for Alkaptonuria.”

DevelopAKUre will also, thereby, contribute to the goal of the International Rare Diseases Research Consortium of achieving 200 new therapies by 2020.